Currently the treatment outcome of malignant glial brain tumors in adult and pediatric patients is poor. Mutations of the tumor suppressor, PTEN, a dual specificity protein phosphatase which dephosphorylates acidic peptides and inositol phospholipids, accompany progression of pediatric and adult brain tumors from benign to the most malignant forms. Brain tumor progression, particularly in aggressive and malignant brain tumors, is associated with augmented proliferation and the induction of angiogenesis. Our preliminary data support the hypothesis that PTEN regulates brain tumor progression by modulating the angiogenic response. U87MG glioma cells stably reconstituted with PTEN cDNA were tested for growth in a nude mouse orthotopic brain tumor model. We observed that the introduction of wild type PTEN resulted in decreased tumor growth in vivo and prolonged survival in mice implanted intracranially with these cells. These changes correlated with diminished phosphorylation of AKT within the PTEN-reconstituted tumor and diminished angiogenic activity, as determined by microvessel density and augmented thrombospondin 1 expression. These effects were not observed in tumors reconstituted with the G129E mutant form of PTEN in which lipid phosphatase activity is ablated. These data support our hypothesis and indicate that, in addition to the reported effects of PTEN on proliferation and cell survival, loss of PTEN regulates tumor-induced angiogenesis and the progression of gliomas to a malignant phenotype via the regulation of phosphoinositide-dependent signals. Based on our preliminary data we propose to evaluate the role of PTEN and PI-3 kinase in brain tumor progression as it relates to the angiogenic response and to determine if PI-3 kinase inhibitors can block brain tumor growth, the angiogenic response and promote survival. These experiments will provide important preclinical data to support the development of PI-3 kinase inhibitors for the treatment of malignant glial tumors associated with a deregulated PI-3 kinase/AKT signaling axis.